1. Field of the Invention
The present invention is related to novel possesses of making lapatinib and lapatinib ditosylate, and novel intermediates thereof. Lapatinib has the structural formula (I) and chemical name N[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine.

2. Description of the Related Art
Lapatinib is a tyrosine kinase inhibitor that is used as an orally administered drug as its ditosylate salt to treat certain types of advanced or metastatic breast cancer and other solid tumors. Lapatinib ditosylate was approved by the FDA in 2007 and the EMEA in 2008 and is marketed by GlaxoSmithKline (GSK) under the trade name of Tykerb® in the USA and Tyverb® in Europe.
Lapatinib substance is claimed in U.S. Pat. No. 6,713,485 B2 and U.S. Pat. No. 6,727,256 B1 and lapatinib ditosylate and its crystalline forms are claimed in U.S. Pat. No. 7,157,466 B2. A synthesis of lapatinib that utilises a palladium mediated coupling of a substituted 4-anilino-6-iodo-quinazoline (II) with a 2-(tributylstannyl)furan (IIIa) is disclosed in U.S. Pat. No. 6,727,256 B1 and is also presented in U.S. Pat. No. 7,157,466 B2. In U.S. Pat. No. 7,157,466 B2 a second generation approach was disclosed that utilises a palladium catalysed coupling of a substituted 4-anilino-6-iodo-quinazoline (II) with furan-2-yl-boronic acids (IIIb). Following the palladium catalysed coupling reactions utilised in the two synthetic methods of U.S. Pat. No. 6,727,256 B1 and U.S. Pat. No. 7,157,466 B2, only one (U.S. Pat. No. 7,157,466 B2) or two (U.S. Pat. No. 6,727,256 B1 and U.S. Pat. No. 7,157,466 B2) synthetic modification of the structure are utilised before the lapatinib substance is provided (Scheme 1). The EMEA's Committee For Medicinal Products For Human Use (CHMP) has published guidelines titled Guideline On The Specification Limits For Residues Of Metal Catalysts Or Metal Reagents and recommendations are presented for oral exposure to metals, including palladium. For a drug being consumed in quantities not exceeding a 10 g daily dose, a limit of 10 ppm (parts per million) concentration of palladium in the drug substance is recommended. Given this, there is still an unmet need for an alternative synthetic method that can be used for preparation of lapatinib in which the palladium mediated coupling step is performed early in the synthetic route, thereby being capable to provide lapatinib and lapatinib tosylate or other salts with consistently low levels of palladium.
